Document Detail

Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus.
MedLine Citation:
PMID:  17664401     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: ARX is a paired-type homeobox gene located on the X chromosome that contains five exons with four polyalanine (PolyA) tracts, a homeodomain, and a conserved C-terminal aristaless domain. Studies in humans have demonstrated remarkable pleiotropy: malformation phenotypes are associated with protein truncation mutations and missense mutations in the homeobox; nonmalformation phenotypes, including X-linked infantile spasms (ISS), are associated with missense mutations outside of the homeobox and expansion of the PolyA tracts. OBJECTIVE: To investigate the role of ARX, we performed mutation analysis in 115 boys with cryptogenic ISS. This included two pairs of brothers. RESULTS: We found an expansion of the trinucleotide repeat that codes for the first PolyA tract from 10 to 17 GCG repeats (c.333_334ins[GCG]7) in six boys (5.2%) ages 2 to 14, from four families, including the two pairs of brothers. In addition to ISS, all six boys had severe mental retardation and generalized dystonia that appeared around the age of 6 months and worsened, eventually leading to stable severe quadriplegic dyskinesia within age 2 years. Three children experienced recurrent, life-threatening status dystonicus. In four children brain MRI showed multiple small foci of abnormal cavitation on T1 and increased signal intensity on T2 in the putamina, possibly reflecting progressive multifocal loss of tissue. CONCLUSION: The phenotype of infantile spasms with severe dyskinetic quadriparesis increases the number of human disorders that result from the pathologic expansion of single alanine repeats. ARX gene testing should be considered in boys with infantile spasms and dyskinetic cerebral palsy in the absence of a consistent perinatal history.
R Guerrini; F Moro; M Kato; A J Barkovich; T Shiihara; M A McShane; J Hurst; M Loi; J Tohyama; V Norci; K Hayasaka; U J Kang; S Das; W B Dobyns
Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Neurology     Volume:  69     ISSN:  1526-632X     ISO Abbreviation:  Neurology     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-07-31     Completed Date:  2007-08-24     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0401060     Medline TA:  Neurology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  427-33     Citation Subset:  AIM; IM    
Department of Pediatric Neurosciences, Pediatric Hospital A Meyer and University of Florence, Firenze, Italy.
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MeSH Terms
Alanine / genetics
Atrophy / genetics,  pathology,  physiopathology
Basal Ganglia / abnormalities,  pathology,  physiopathology
Child, Preschool
DNA Mutational Analysis
Dystonic Disorders / genetics*,  metabolism,  physiopathology
Genetic Markers / genetics
Genetic Testing
Homeodomain Proteins / genetics*
Infant, Newborn
Magnetic Resonance Imaging
Mental Retardation / genetics*,  metabolism,  physiopathology
Mutation / genetics*
Spasms, Infantile / genetics*,  metabolism,  physiopathology
Transcription Factors / genetics*
Trinucleotide Repeat Expansion / genetics*
Reg. No./Substance:
0/ARX protein, human; 0/Genetic Markers; 0/Homeodomain Proteins; 0/Transcription Factors; 56-41-7/Alanine
Comment In:
Neurology. 2007 Jul 31;69(5):421-2   [PMID:  17664398 ]

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